Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
  • C07D239/52—Two oxygen atoms
  • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
  • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/557—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. orotic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

• This invention relates to compounds which can act as inhibitors of viral polymerases, especially the hepatitis C virus (HCV) polymerase, to uses of such compounds and to their preparation.
• HCV hepatitis C virus
• HCV hepatitis C virus
• NANB-H sporadic non-A, non-B hepatitis
• Some 1% of the human population of the planet is believed to be affected. Infection by the virus can result in chronic hepatitis and cirrhosis of the liver, and may lead to hepatocellular carcinoma.
• RNA-dependent RNA polymerase plays an essential role in replication of the virus and is therefore an important target in the fight against hepatitis C.
• HCV hepatitis C virus
• the present invention provides a compound of formula (I) below, or a pharmaceutically acceptable salt thereof:
• Z represents C2-6 alkynyl, aryl or heteroaryl, any of which groups may be optionally substituted;
• R 1 represents Ci- ⁇ alkyl or aryl(C ⁇ -6)alkyl, either of which groups may be optionally substituted;
• R 2 represents hydrogen; or CI-G alkyl, C2-6 alkylcarbonyl, aryl, arylcarbonyl, heteroaryl, aryl(C 1 -6)alkyl or heteroaryl(C ⁇ -6)alkyl, any of which groups may be optionally substituted; and
• R 3 represents hydrogen, C1.6 alkyl, C3-7 heterocycloalkyl(C 1 -6)alkyl, di(C 1- 6)alkylamino(C 1 -G)alkyl, C2-6 alkylcarbonyloxy(C 1 - ⁇ )alkyl or C 3 - 7 cycloalkoxycarbonyloxy(Ci- 6 )alkyl; for use in therapy, especially for pharmaceutical use in humans.
• the present invention also provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof; provided that, when Z is unsubstituted phenyl, then R 1 , R 2 and R 3 do not each simultaneously represent methyl.
• Ci- ⁇ alkyl groups include methyl and ethyl groups, and straight-chained or branched propyl, butyl, pentyl and hexyl groups. Particular alkyl groups are methyl, ethyl, /i-propyl, isopropyl, tert- butyl and 1,1-dimethylpropyl. Derived expressions such as "Ct-e alkoxy" are to be construed accordingly.
• C2-6 alkenyl groups include vinyl, allyl and dimethylallyl groups.
• C2-6 alkynyl groups include ethynyl and propargyl groups.
• Typical C3-7 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
• Suitable C3-7 heterocycloalkyl groups include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl groups.
• Suitable aryl groups include phenyl and naphthyl, especially phenyl.
• Suitable heteroaryl groups include pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzthienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, oxadiazoiyl, thiadiazolyl, triazolyl and tetrazolyl groups.
• Typical aryl(C 1 -6)alkyl groups include benzyl, phenylethyl, phenylpropyl, phenylbutyl and naphthylmethyl.
• Typical heteroaryl(C 1- G)alkyl groups include furylmethyl, furylethyl, thienylmethyl, thienylethyl, oxazolylmethyl, oxazolylethyl, thiazolylmethyl, thiazolylethyl, imidazolylmethyl, imidazolylethyl, oxadiazolylmethyl, oxadiazolylethyl, thiadiazolylmethyl, thiadiazolylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl, tetrazolylethyl, pyridinylmethyl, pyridinylethyl, pyrimidinylmethyl, pyrazinylmethyl, quin
• substituents are not particularly limited and may, for instance, be selected from CI-G alkyl, C2- 6 alkenyl, C3-7 cycloalkyl, C3-7 heterocycloalkyl, aryl, aryl(C 1 -G)alkyl, heteroaryl, heteroaryl(C ⁇ -G)alkyl, C1-6 alkoxy, aryloxy, aryl(C 1- 6)alkoxy, heteroaryloxy, heteroaryl(Ci-6)alkoxy, amino, nitro, halo, hydroxy, carboxy, formyl, cyano and trihalomethyl groups.
• optional substituents may be attached to the compounds or groups which they substitute in a variety of ways, either directly or through a connecting group of which the following are examples: amine, amide, ester, ether, thioether, sulphonamide, sulphamide, sulphoxide, urea, thiourea and ure thane.
• an optional substituent may itself be substituted by another substituent, the latter being connected directly to the former or through a connecting group such as those exemplified above.
• the compounds according to the invention have at least one asymmetric centre, they may accordingly exist as enantiomers.
• the compounds according to the invention possess two or more asymmetric centres, they may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present invention.
• moiety Z in the compounds of formula (I) above represents optionally substituted C2-G alkynyl
• this is suitably an optionally substituted ethynyl group.
• a typical substituent on the C 2 - G alkynyl group is tri(C ⁇ -6)alkylsilyl, especially trimethylsilyl.
• a typical value for the moiety Z is trimethylsilylethynyl.
• Z represents an optionally substituted aryl or heteroaryl moiety
• it may suitably be selected from phenyl, thienyl, oxazolyl, thiazolyl, furyl, isoquinolinyl, indolyl, isoxazolyl, pyrazolopyrimidinyl and pyrazinyl, any of which groups may be optionally substituted.
• Particular values of Z include phenyl, thienyl, thiazolyl and furyl, any of which groups may be optionally substituted. These groups may be joined to the 2-position of the pyrimidinone nucleus at any available position of the aryl or heteroaryl ring. However, connection at certain positions may be preferred and this is considered in some more detail below.
• Preferred optional substituents on the aryl or heteroaryl group Z may be selected from a wide variety of groups. For instance, they may be simple, relatively small groups such as halogen (especially fluorine, chlorine and bromine), hydroxy, -NO2, -NH2, formyl, C2-6 alkylcarbonyl, -CO2H, C2-6 alkoxycarbonyl, C ⁇ -6 alkyl (especially methyl), C2-6 alkenyl, C2- 0 alkynyl, -CN, C ⁇ -6 alkoxy (especially methoxy), C1-6 alkylthio (especially methylthio), CI- G alkylsulfinyl (especially methylsulfinyl) or CI- G alkylsulfonyl (especially methylsulfonyl). As appropriate any of these substituents may be substituted by one or more of the others. However, in general at least one substituent is a group of formula (II):
• R 4 is a generally hydrophobic moiety containing one or more, but generally at least 3, preferably 4 to 20, particularly 4 to 14, carbon atoms.
• R 4 includes one or more of the following groups, any of which may, optionally, be substituted: aryl, aryl(C 1 .6)alkyl, C3-7 cycloalkyl, C1. 6 alkyl (especially branched C1-6 alkyl), he teroaryKCi-G) alkyl, C3-7 heterocycloalkyl and C2-6 alkenyl.
• the group X is preferably selected from -NH-SO2-, -NH-SO2-NH-, -CH2-SO2-, -SO2-NH-, -NH-CO-NH-, -NH-CS-NH-, -NH-CO-O-, -NH-CO-, -CO-NH-, -NH-CO-NH-SO2-, -NH-CO-NH-CO-, -0-, -S-, -SO-, -SO2-, -NH-, -CH 2 -, -CH2O- and -CH2S-.
• the hydrogen atom of any NH group may, optionally, be replaced b ⁇ a C1-6 alkyl group.
• R 1 represents optionally substituted aryl(C ⁇ -6)alkyl, this may be benzyl or phenylethyl, either of which groups may be optionally substituted.
• a particular substituent in this regard is halogen, especially chloro.
• R 1 examples include methyl, ethyl, trifluoroethyl (particularly 2,2,2-trifluoroethy ⁇ ), benzyl, carboxybenzyl and chlorophenylethyl, especially methyl.
• Typical values of R 2 include hydrogen; and CI-G alkyl, C 2 -G alkylcarbonyl, arylcarbonyl or aryl(C ⁇ -6) alkyl, any of which groups may be optionally substituted.
• Particular values of R 2 include hydrogen; and CI - G alkyl, C 2 -G alkylcarbonyl or arylcarbonyl, any of which groups may be optionally substituted.
• R 2 examples include halogen and Ct-c alkoxy, especially fluoro or methoxy.
• Particular values of R 2 include hydrogen, methyl, ethyl, tert-butyl, acetyl, pivaloyl, benzoyl, benzyl, difluorobenzyl and methoxybenzyl.
• R 2 examples include hydrogen, methyl, ethyl, tert-butyl, acetyl, pivaloyl or benzyl.
• R 2 represents hydrogen
• R 3 include hydrogen, methyl, ethyl, morpholinylethyl, dimethylaminoethyl, acetoxymethyl, pivaloyloxymethyl and 1 - (cyclohexyloxycarbonyloxy)ethyl.
• R 3 include hydrogen, methyl and ethyl.
• R 3 represents hydrogen
• Z 1 represents optionally substituted aryl
• R 1 is as defined above.
• examples of compounds within this class are those of formula (IN):
• R 1 is as defined above; and each of R 5 and R G may independently be selected from H or a substituent group.
• one of R 5 and R 6 is hydrogen, while the other is a substituent.
• a substituent may be at any of the 2-, 3- or 4-positions - i.e. ortho, meta or para to the pyrimidinone nucleus. However, where a single substituent is present, substitution at the ortho or meta positions is preferred.
• the substituents R 5 and R 6 may be selected from a wide variety of groups. For instance, they may be simple, relatively small groups such as halogen (especially fluorine, chlorine and bromine), hydroxy, -NO2, -NH2, formyl, C 2 -G alkylcarbonyl, -CO2H, C2-6 alkoxycarbonyl, C1-6 alkyl (especially methyl), C2-6 alkenyl, C2-6 alkynyl, -CN, C1-6 alkoxy (especially methoxy), CI- G alkylthio (especially methylthio), CI-G alkylsulfinyl (especially methylsulfinyl) or CI-G alkylsulfonyl (especially methylsulfonyl). As appropriate any of these substituents may be substituted by one or more of the others.
• substituent R 5 and/or R 6 include a relatively hydrophobic group R 4 which is bonded to the phenyl group through a hnkage X.
• substituents R 5 and/or R G may be represented by the formula (II):
• R 4 and X are as defined above.
• examples of preferred classes of compound are those in which a single ortho or meta substituent is present, and that substituent is selected from the following formulae (V), (VI), (VII), (VIII) and (IX):
• n is zero or an integer from 1 to 6, and preferably is from zero to 3, especially 0 or 1; m is zero or an integer from 1 to 6, but preferably is 0 or 1; each of p and q is independently 0 or 1, but preferably they are not simultaneously 1; r is an integer from 1 to 6, preferably 1;
• R 7 is an optionally substituted aryl, heteroaryl, C3-7 cycloalkyl, C 3 - heterocycloalkyl or branched CI-G alkyl group; each R 8 is independently a CI -G alkyl group (especially methyl), a C3-7 cycloalkyl group, an optionally substituted aryl group (especially phenyl), hydroxy or hydroxy(C 1 -6)alkyl (especially hydroxymethyl), any of which may be optionally etherified, or -NH2, optionally protonated, alkylated or derivatised as a urethane group; and Y is selected from -0-, -S- and -NH-.
• linkage X may be any of the X groups specified above.
• sulfonamide (-NH-SO2-), urea (-NH-CO-NH-), urethane (-NH-CO-O-) and amide (-NH-CO-) groups are favoured.
• a particular value of X is -NH-CO-NH-SO2-.
• the group R 7 is preferably an aryl or heteroaryl group, of which optionally substituted phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl and thiazolyl are particularly preferred examples. Each of these may, optionally, be substituted by another optionally substituted aryl or heteroaryl group of the same or different type.
• Typical compounds of formula (II) are specifically exemplified herein as Examples 24-26, 36 and 37. All those compounds have ICso values below 100 ⁇ M when measured in the assay described below.
• Z 2 represents optionally substituted heteroaryl
• R 1 , R 2 and R 3 are as defined above.
• Z 2 particularly values include thienyl, thiazolyl and furyl, especially thienyl, any of which groups may be optionally substituted.
• Preferred compounds in this sub-class are those in which the heteroaryl group Z 2 is unsubstituted, or carries a single substituent R 9 , as defined infra.
• R 1 , R 2 and R 3 are as defined above;
• R 9 is as defined infra.
• the pyrimidinone nucleus and the R 9 substituent may be at any position on the thiophene ring. However, it is preferred that when the pyrimidinone is at position 2 on the thiophene ring, then substituent R 9 is at the 3-position, substitution at the 4- or 5-positions being less preferred. When the pyrimidinone group is at the 3-position of the thiophene ring, then R 9 is preferably at the 2- or 4-position of the thiophene ring, more preferably at the 4-position.
• favoured compounds in accordance with the present invention are represented by formula (XII) and (XIII) below:
• R 1 , R 2 and R 3 are as defined above;
• R 9 is as defined infra.
• Substituent R 9 may be selected from a wide variety of groups. For instance, like substituents R 5 and R G discussed above it may be a simple, relatively small group such as halogen (especially fluorine, chlorine and bromine), hydroxy, -NO2, -NH2, formyl, C2-G alkylcarbonyl, -CO2H, C 2 G alkoxycarbonyl, CI.G alkyl (especially methyl), Ci- ⁇ alkenyl, C2-6 alkynyl, -CN, Ci-G alkoxy (especially methoxy), Ct- ⁇ alkylthio (especially methylthio), C ⁇ -6 alkylsulfinyl (especially methylsulfinyl) or Ci- ⁇ alkylsulfonyl (especially methylsulfonyl). As appropriate any of these substituents may be substituted by one or more of the others.
• R 9 includes a relatively hydrophobic group which is bonded to the thienyl group through a linkage X.
• the group R 9 may be represented by the formula (II):
• Preferred X groups are amide, sulphonamide, urea and urethane linkages.
• a particularly preferred X group is -NH-CO-NH-SO2-.
• Preferred R 4 groups are those shown in formulae (V) to (IX) already discussed above, and which include a group R 7 .
• R 4 is naphthyl.
• R 7 groups are aromatic groups, especially phenyl, naphthyl, thienyl, pyridyl, benzothienyl, indolyl, benzimidazolyl and oxazolyl groups.
• R 7 comprises fused aromatic rings, the connection to the remainder of the R 4 group may be through any ring.
• R 7 Preferred optional substituents on R 7 , especially in the case where R 7 is an aryl group, include halogen (e.g. fluorine, chlorine and/or bromine), nitro (-NO2), C ⁇ -6 alkyl (especially methyl), Ci-e alkoxy (especially methoxy), trifluoromethyl and aryl (especially phenyl).
• halogen e.g. fluorine, chlorine and/or bromine
• nitro nitro
• C ⁇ -6 alkyl especially methyl
• Ci-e alkoxy especially methoxy
• trifluoromethyl especially aryl
• aryl especially phenyl
• n is zero.
• R 7 is naphthyl
• Typical compounds of formula (X) are specifically exemplified herein as Examples 1-23, 27-35, 38-40 and 42-49. Those compounds all have ICso values of less than 100 ⁇ M as measured in the assay described infra. In fact, most have an IC50 of less than 25 ⁇ M, frequently less than 10 ⁇ M. Certain of the compounds have submicromolar ICso values.
• the invention provides the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treatment or prevention of infection by hepatitis C virus in a human or animal.
• a further aspect of the invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.
• the composition may be in any suitable form, depending on the intended method of administration. It may for example be in the form of a tablet, capsule or liquid for oral administration, or of a solution or suspension for administration parenterally.
• compositions optionally also include one or more other agents for the treatment of viral infections such as an antiviral agent, or an immunomodulatory agent such as ⁇ -, ⁇ - or ⁇ -interferon.
• agents for the treatment of viral infections such as an antiviral agent, or an immunomodulatory agent such as ⁇ -, ⁇ - or ⁇ -interferon.
• the invention provides a method of inhibiting hepatitis C virus polymerase and/or of treating or preventing an illness due to hepatitis C virus, the method involving administering to a human or animal (preferably mammalian) subject suffering from the condition a therapeutically or prophylactically effective amount of the pharmaceutical composition described above or of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof.
• Effective amount means an amount sufficient to cause a benefit to the subject or at least to cause a change in the subject's condition.
• the dosage rate at which the compound is administered will depend on a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age of the patient, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition and the host undergoing therapy. Suitable dosage levels may be of the order of 0.02 to 5 or 10 g per day, with oral dosages two to five times higher. For instance, administration of from 10 to 50 mg of the compound per kg of body weight from one to three times per day may be in order. Appropriate values are selectable by routine testing. The compound may be administered alone or in combination with other treatments, either simultaneously or sequentially.
• it may be administered in combination with effective amounts of antiviral agents, immunomodulators, anti-infective s or vaccines known to those of ordinary skill in the art. It may be administered by any suitable route, including orally, intravenously, cutaneously and subcutaneously. It may be administered directly to a suitable site or in a manner in which it targets a particular site, such as a certain type of cell. Suitable targeting methods are already known.
• An additional aspect of the invention provides a method of preparation of a pharmaceutical composition, involving admixing at least one compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable adjuvants, diluents or carriers and/or with one or more other therapeutically or prophylactically active agents.
• the compounds according to the present invention may be prepared by a process which comprises reacting a compound of formula (XIV) with a compound of formula (XV):
• L 1 represents a suitable leaving group.
• the leaving group L 1 is typically a halogen atom, e.g. iodo; or a sulphate moiety, e.g. methoxysulphonyloxy.
• the reaction is conveniently effected in the presence of a base, e.g. caesium carbonate or lithium hydride; in a suitable solvent such as tetrahydrofuran or 1,4-dioxane.
• Amidoximes of formula (XVI) may be prepared by reacting a compound of formula (XVII) with a compound of formula (XVffl):
• Amidoximes of formula (XVII) may be prepared by reacting hydroxylamine with a nitrile of formula Z-CN; typically in the presence of a base such as sodium carbonate, potassium carbonate or triethylamine.
• the compounds according to the invention may be prepared by a process which comprises reacting a compound of formula (XVIII) as defined above with a compound of formula (XIX):
• reaction between compounds (XVIII) and (XIX) is conveniently accomplished in a suitable solvent, which will typically be a chlorinated solvent such as chloroform or dichloromethane. Cyclisation of the ensuing intermediate is suitably effected by heating in xylene.
• the intermediates of formula (XIX) may be prepared by reacting a compound of formula R x -NHOH with a nitrile of formula Z-CN; typically in the presence of a base such as sodium carbonate.
• Nitriles of formula Z-CN may be obtained from commercial sources or may be prepared from the corresponding primary amides of formula Z-CONH2 using established methods known to those skilled in the art.
• Primary amides of formula Z-CONH2 may be obtained from commercial sources or may be prepared from the corresponding esters or carboxylic acids using established methods known to those skilled in the art.
• the compounds according to the invention may be prepared by a process which comprises reacting a compound of formula (XVIII) as defined above with a compound of formula (XX):
• the intermediates of formula (XX) may be prepared by reacting a compound of formula R 1 -NH2 with a compound of formula (XXI):
• the intermediates of formula (XXI) may be prepared by reacting hydroxylamine with a compound of formula Z-CHO; followed by treating the oxime thereby obtained with N-chlorosuccinimide.
• the compounds according to the invention may be prepared by reacting a compound of formula Z-B(OH) 2 with a compound of formula (XXII):
• the leaving group L 2 is typically a halogen atom, e.g. chloro.
• the transition metal catalyst of use in the foregoing reaction is suitably bis(tri-tert-butylphosphine)palladium(0) or tetrakis- (triphenylphosphine)palladium(O).
• a compound of formula (I) wherein R 2 represents hydrogen may be converted into the corresponding compound wherein R 2 is other than hydrogen by means of conventional etherification or esterification procedures.
• a compound of formula (I) wherein R 2 represents CI-G alkyl, e.g. ethyl, may be converted into the corresponding compound wherein R 2 represents hydrogen by treatment with boron tribromide.
• a compound of formula (I) wherein R 2 represents t ⁇ rt-butyl may be converted into the corresponding compound wherein R 2 represents hydrogen by treatment with trifluoroacetic acid.
• acetyl, pivaloyl or benzoyl may be converted into the corresponding compound wherein R 2 represents hydrogen by means of standard saponification techniques, e.g. by treatment with an alkaline reagent such as sodium hydroxide or lithium hydroxide.
• a compound of formula (I) wherein R 3 represents hydrogen may be converted into the corresponding compound wherein R 3 is other than hydrogen by means of conventional esterification procedures, e.g. by treatment with the appropriate alcohol of formula R 3 -OH in the presence of a mineral acid such as hydrochloric acid.
• a compound of formula (I) wherein R 3 is other than hydrogen may be converted into the corresponding compound wherein R 3 is hydrogen by means of standard saponification techniques, e.g.
• the desired product can be separated therefrom at an appropriate stage by conventional methods such as preparative HPLC; or column chromatography utilising, for example, silica and/or alumina in conjunction with an appropriate solvent system.
• novel compounds may, for example, be resolved into their component enantiomers by standard techniques such as preparative HPLC, or the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di- -toluoyl-d-tartaric acid and/or (-t-)-di-p-toluoyl-l-tartaric acid, followed by fractional crystallization and regeneration of the free base.
• optically active acid such as (-)-di- -toluoyl-d-tartaric acid and/or (-t-)-di-p-toluoyl-l-tartaric acid, followed by fractional crystallization and regeneration of the free base.
• optically active acid such as (-)-di- -toluoyl-d-tartaric acid and/or (-t-)-di-p-toluoyl-l-tartaric acid, followed by fractional crystallization and regeneration of the
• any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 3rd edition, 1999.
• the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
• the following Examples illustrate the preparation of compounds according to the invention.
• the compounds in accordance with this invention are potent inhibitors of HCV polymerase.
• the ICso values in ⁇ M of these compounds can be measured in the following way.
• WO 96/37619 describes the production of recombinant HCV RdRp from insect cells infected with recombinant baculovirus encoding the enzyme.
• the purified enzyme was shown to possess in vitro RNA polymerase activity using RNA as template.
• the reference describes a polymerisation assay using poly(A) as a template and oligo(U) as a primer.
• Incorporation of tritiated UTP is quantified by measuring acid-insoluble radioactivity.
• the present inventors have employed this assay to screen the compounds of the accompanying Examples as inhibitors of HCV RdRp. Incorporation of radioactive UMP was measured as follows.
• the standard reaction (100 ⁇ l) was carried out in a buffer containing 20 mM tris/HCl pH 7.5, 5 mM MgCl 2 , 1 mM DTT, 50 mM NaCl, 1 mM EDTA, 20U Rnasin (Promega), 0.05% Triton X-100, 1 ⁇ Ci [ 3 H]-UTP (40 Ci/mmol, NEN), 10 ⁇ M UTP and 10 ⁇ g/ml poly(A). 01igo(U) 12 (1 ⁇ g/ml, Genset) was added as a primer. The final NSSB enzyme concentration was 20 nM.
• % residual activity 100/(l+[I]/IC 5 o) s where [I] is the inhibitor concentration and "s" is the slope of the inhibition curve.
• Nuclear magnetic resonance (NMR) spectra were recorded on a Bruker AMX 300 or AMX 400 spectrometer at a temperature of 300 K unless otherwise indicated.
• the chemical shifts ( ⁇ ) are reported in parts per million (ppm) relative to internal tetramethylsilane or the residual solvent peak.
• ⁇ -NMR spectra significant peaks are tabulated in the order number of protons, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; bs, broad singlet), coupling constant(s) in Hertz.
• Mass spectral data were obtained on a Perkin Elmer API 100 in negative (ES ) or positive (ES + ) ionization mode and results are reported as the ratio of mass over charge (mlz) for the parent ion only, followed in many cases by the relative abundance of the ion.
• Organic extracts were usually dried over sodium sulfate, the drying agent was removed by filtration and the solvents evaporated on a rotary evaporator under reduced pressure.
• reaction mixture was stirred for 1 h at 0°C, then treated in one portion with a solution of sodium tetrafluoroborate (1.5 eq) in water (4.8 M).
• the precipitated salt was isolated by filtration, washed with cold 5% aqueous sodium tetrafluoroborate, ethanol and diethyl ether, then dried in the air. The beige solid (81%) thus obtained was used without further purification.
• Activated copper bronze (3 eq; for the activation see Vogel's Textbook of Practical Organic Chemistry, 5th ed., p. 426) was added to a mechanically stirred solution of sodium nitrite (12 eq) in water (6.7 M).
• Step 3 Dimethyl 2-( ⁇ ri-amino-l-(3-nitrothien-2-yl)methylidenel- amino ⁇ oxy)but-2-enedioate
• Step 4 Methyl 5-hvdroxy-2-(3-nitrothien-2-yl)-6-oxo-1.6- dihvdropyrimidine-4-carboxylate
• Step 5 Methyl 5-r(2,2-dimethylpropanoyl)oxy1-6-hvdroxy-2-(3-nitrothien-2- yl)pyrimidine-4-carboxylate
• Step 7 Methyl 5-r(2,2-dimethylpropanoyl)oxy1-l-methyl-2-(3-aminothien- 2-yl)-6-oxo-l,6-dihvdropyrimidine-4-carboxylate
• methanol 0.02 M
• Step 8 2-r3-(ir(2-Chlorobenzyl)amino1carbonyl ⁇ amino)thien-2-yl]-5- hvdroxy-l-methyl-6-oxo-l,6-dihvdro ⁇ yrimidine-4-carboxylic acid
• the crude product obtained after evaporation of the solvents, was directly hydrolyzed using sodium hydroxide (0.5 M, 3 eq) in methanol (0.5 M) at 85°C for 1 h. The solution was cooled to room temperature and acidified to pH 2 with hydrochloric acid (1 N). The crude product was purified by RP-HPLC. After lyophilization 2-[3-( ⁇ [(2- chlorobenzyl)amino]carbonyl ⁇ amino)thien-2-yl]-5-hydroxy-l-methyl-6-oxo- l,6-dihydropyrimidine-4-carboxylic acid was obtained as a colourless powder (38%).
• Step 1 Methyl 5.6-dihvdroxy-2-(thien-2-yl)pyrimidine-4-carboxylate To a solution (1.1 M) of 2-thiophene amidoxime (1.0 eq) in chloroform was added dropwise dimethyl acetylenedicarboxylate (1.02 eq). The mixture was stirred at room temperature for 2 h, and then concentrated in vacuo to give a residue, which was taken up inp-xylene. The resulting solution (1.3 M) was heated at reflux for 5 h, then cooled to room temperature. The precipitate was collected by filtration, washed with methanol and diethyl ether and crystalhzed from acetic acid to afford the title compound (26%).
• Step 7) and phenyl isocyanate ⁇ H (400 MHz; DMSO-de) 3.41 (3H, s), 6.97 (IH, t, 7.6), 7.27 (2H, t, 7.6), 7.42 (2H, d, 7.6), 7.68 (IH, d, 5.6), 7.72 (IH, d, J .Q), 8.70 (IH, bs), 9.40 (IH, bs); mlz (ES ) 385 (M-H)-, 100%.
• Example 1 Step 8 Following generally the procedures described in Example 1, Step 8, the title compound was obtained from methyl 5-[(2,2- dimethylpropanoyl)oxy]-l-methyl-2-(3-aminothien-2-yl)-6-oxo-l,6- dihydropyrimidine-4-carboxylate (obtained as described in Example 1, Step 7) and 2-biphenylyl isocyanate (14%).
• Example 1, Step 8 the title compound was obtained from methyl 5-[(2,2- dimethylpropanoyl)oxy]-l-methyl-2-(3-aminothien-2-yl)-6-oxo-l,6- dihydropyrimidine-4-carboxylate (obtained as described in Example 1, Step 7), and 2-phenylethyl isocyanate (28%).
• Example 1, Step 8 the title compound was obtained from methyl 5-[(2,2- dimethylpropanoyl)oxy]-l-methyl-2-(3-aminothien-2-yl)-6-oxo-l,6- dihydropyrimidine-4-carboxylate (obtained as described in Example 1, Step 7) and isobutyl chloroformate, using triethylamine as the base (18%).
• Dioxane was evaporated in vacuo, the residue dissolved in ethyl acetate and the organic phase washed with water (lx), hydrochloric acid (1 N, lx), water (lx) and brine (lx), and dried. Evaporation of the solvent afforded a brown solid (95%) which was dissolved in dichloromethane (0.3 M solution).
• Triethylamine 2.5 eq was added and the solution cooled at 0°C with an ice-bath. Trifluoroacetic anhydride was added dropwise and the mixture was stirred at room temperature for 1 h.
• Step 2 2-(3-r2-(Benzyloxy)ethyllthien-2-yll-5-hvdroxy-l-methyl-6-oxo-1.6- dihydropyrimidine-4-carboxylic acid
• the title compound was prepared from the foregoing nitrile as described in Example 1, Steps 2-6 and 8 and was obtained as a white powder (3% overall) after purification by RP-HPLC and lyophihzation.
• Step 2 tert-Butyl ⁇ 4-[aminou ydroxyimino)methvnthien-3-yllcarbamate
• Step 3 Methyl 2- ⁇ 4-[(t ⁇ rt-butoxycarbonyl)amino]thien-3-yl>-5,6- dihydroxypyrimidine-4-carboxylate
• Example 1 Generally following the procedure in Example 1, Step 5, the title compound was obtained from methyl 2- ⁇ 4-[(tert- butoxycarbonyl)amino]thien-3-yl ⁇ -5,6-dihydroxypyrimidine-4-carboxylate (1.0 eq) in pyridine and pivaloyl chloride (1.0 eq) as a brown solid (100%) after workup and was used without further purification.
• Step 5 Methyl 2- ⁇ 4-r(t ⁇ rt-butoxycarbonyl)amino1thien-3-yl)-5-r(2.2- dimethylpropanoyl)oxyl-l-methyl-6-oxo-1.6-dihvdropyrimidine-4- carboxylate
• Methyl 2-(3-aminothien-2-yl)-5-[(2,2-dimethylpropanoyl)oxy]-l- methyl-6-oxo-l,6-dihydropyrimidine-4-carboxylate obtained as described in Example 1, Step 7) was dissolved in anhydr. acetonitrile and the resulting solution (0.03 M) was treated dropwise with 2- chlorobenzenesulfonyl isocyanate (1.1 eq). The mixture was stirred at room temperature for 30 minutes, then concentrated in vacuo. The residue was washed with diethyl ether to give a solid, which was taken up in a 1:1 mixture of MeOH and dioxane.
• Step 1 Methyl 5-(benzoyloxy)-6-hvdroxy-2- ⁇ 3-r( ' 4- methoxybenzyl)oxy1phenyl ⁇ pyrimidine-4-carboxylate
• Step 2 Methyl 5-(benzoyloxy)-2- ⁇ 3-[(4-methoxybenzyl)oxylphenyl ⁇ -l- methyl-6-oxo-l,6-dihvdropyrimidine-4-carboxylate
• Methyl 5-(benzoyloxy)-2- ⁇ 3-[(4-methoxybenzyl)oxy]phenyl ⁇ -l-methyl- 6-oxo-l,6-dihydropyrimidine-4-carboxylate was suspended in a 4:1 mixture of DCM and TFA (0.1 M). After 30 min the volatiles were evaporated and the remaining solid was triturated with diethyl ether to obtain the title product.
• Step 4 5-Hvdroxy-2-(3-hvdroxyphenyl)-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxylic acid
• Methyl 5-(benzoyloxy)-2-(3-hydroxyphenyl)-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxylate was suspended in 0.5 N NaOH and stirred overnight at 80°C. After cooling down to room temperature and addition of 1 N HC1, the title product precipitated as a white solid, and was filtered off and dried under vacuum.
• Step 1 Methyl 5- (2.2-dimethylpropanoyl)oxy]-6-hvdroxy-2-(3- nitrophenyl)pyrimidine-4-carboxylate This compound was obtained from 3-nitrobenzonitrile following essentially the procedures described in Example 1, Steps 2-6.
• ⁇ H 400 MHz; DMSO-de) 1.31 (9H, s), 3.87 (3H, s), 7.85 (IH, t, 8.0), 8.44 (IH, d, 8.0), 8.52 (IH, d, / 8.0), 8.93 (IH, s); mlz (ES + ) 376 (M+H) + .
• Step 2 Methyl 5- (2.2-dimethylpropanoyl)oxyl-l-methyl-2-(3-nitrophenylV 6-oxo-l,6-dihvdropyrimidine-4-carboxylate
• Step 3 Methyl 2-(3-aminophenyl)-5-r(2,2-dimethylpropanoyl)oxy1-l- methyl-6-oxo-1.6-dihydropyrimidine-4-carboxylate
• Step 2 Methyl 5-(2-methoxy-2-oxoethyl)-2-methyl-3-(3-nitrothien-2-yl)-2.5- dihydro- 1 , 2, 4-oxadiazole - 5-carboxylate
• Step 4 Methyl 5-(acetyloxyVl-methyl-2-(3-nitrothien-2-yl)-6-oxo-1.6- dihydropyrimidine-4-carboxylate
• Triethylamine (2.2 eq) and acetic anhydride (2 eq) were added to a solution of the foregoing compound (1 eq) in dichloromethane (0.2 M) and the reaction mixture was stirred for 16 h at room temperature. The mixture was then diluted with dichloromethane and washed with hydrochloric acid (1 N), sat. aqu. NaHC03, and brine. After removal of the volatiles, the title compound was obtained as a pale yellow solid (97%), which was used without further purification.
• Step 5 Methyl 5-(acetyloxy)-2-(3-aminothien-2-yl)-l-methyl-6-oxo-1.6- dihydropyrimidine-4-carboxylate Pd/C (10% Pd, 20% in weight) was added to a solution (0.1 M) of methyl 5-(acetyloxy)-l-methyl-2-(3-nitrothien-2-yi)-6-oxo-l,6- dihydropyrimidine-4-carboxylate in ethyl acetate. The reaction mixture was stirred under an atmosphere of hydrogen for 2 h at room temperature.
• Step 6 2- ⁇ 3-r(Benzylsulfonyl)amino1thien-2-yl
• Triethylamine (6 eq) and benzylsulfonyl chloride (4 eq) were added to a solution of methyl 5-(acetyloxy)-2-(3-aminothien-2-yl)-l-methyl-6-oxo- l,6-dihydropyrimidine-4-carboxylate in acetonitrile (0.1 M).
• the reaction mixture was stirred for 16 h at room temperature. After dilution with ethyl acetate, the organic layer was washed with hydrochloric acid (1 N), sat. aqu. NaHCO ⁇ , and brine.
• Methyl 5-(acetyloxy)-2- ⁇ 3- [(benzylsulfonyl)amino]thien-2-yl ⁇ -l-methyl-6-oxo-l,6-dihydropyrimidine- 4-carboxylate was obtained as a pale yellow solid (60%), which was dissolved (0.05 M solution) at room temperature in a 2:1 mixture of 1,4- dioxane and sodium hydroxide (1 N). The reaction mixture was stirred at 75°C for 2 h, and then cooled to room temperature and acidified to pH 2 with hydrochloric acid (1 N).
• Step 3 Methyl 2-(3-formylthien-2-yl)-5-hvdroxy-l-methyl-6-oxo-1.6- dihydropyrimidine-4-carboxylate To a mixture of 3-(l,3-dioxolan-2-yl)- ⁇ -hydroxy- ⁇ r -methylthiophen-
• Step 4 Methyl 5-r(2.2-dimethylpropanoyl)oxy1-2-(3-formylthien-2-yl)-l- methyl-6-oxo-l,6-dihvdropyrimidine-4-carboxylate
• Step 5 2-(3-Formylthien-2-yl)-5-hvdroxy-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxylic acid
• Step 1 Methyl 5-r(2,2-dimethylpropanoyl)oxyl-2-(3-carboxythien-2-yl)-l- methyl-6-oxo-l,6-dihvdropyrimidine-4-carboxylate
• Step 2 2-(3-Carboxythien-2-yl)-5-hvdroxy-l-methyl-6-oxo-l,6- dihvdropyrimidine-4-carboxylic acid
• Step 1 Methyl 5-tert-butoxy-2-(3-formylthien-2-yl)-l-methyl-6-oxo-1.6- dihvdropyrimidine-4-carboxylate
• Step 2 Methyl 5-fer ⁇ butoxy-l-methyl-6-oxo-2-r3-(2-phenylethenyl)thien-2- yl] - 1 , 6-dihydrop yrimidine-4-carboxylate
• Step 3 Methyl 5-hvdroxy-l-methyl-6-oxo-2-r3-(2-phenylethenyl)thien-2-yll- l,6-dihvdropyrimidine-4-carboxylate
• the required phosphonium salt was synthesized in three steps from 3-(2- chlorophenyl)propionic acid by reduction to the alcohol, conversion to the bromide, and reaction with triphenylphosphine. After the Wittig reaction, the product was deprotected as described in Example 32, Step 3. It was then converted completely into the E isomer by dissolving it in benzene (0.1 M solution), containing a few crystals of iodine, and irradiating the solution for 9 h with a sun lamp (400 Watt).
• Example 33 Following generally the procedures of Example 32, Steps 1 and 2, and then the procedures of Example 33 the title compound was obtained as a white solid (21% overall) from methyl 5-tert-butoxy-2-(3-formylthien- 2-yl)-l-methyl-6-oxo-l,6-dihydropyrimidine-4-carboxylate and 3- phenylpropyl(triphenyl)phosphonium bromide.
• the Wittig reaction was carried out in DCM at 50°C, using potassium tert-butoxide as the base.
• the starting nitrile was obtained by alkylation of 2- hydroxybenzonitrile (1 eq) in DMF with 3,4-dichlorobenzyl chloride (0.9 eq), using K2CO 3 (2 eq) as the base. The mixture was kept at 60°C overnight. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and hydrochloric acid (1 N). The organic phase was washed with NaOH (1 N) and brine.
• Step 1 Ethyl 2-ethoxy-2-(l-methyl-2,5-dioxoimidazolidin-4-ylidene)- ethanoate
• Step 2 5-Ethoxy-2-hvdroxy-l-methyl-6-oxo-1.6-dihvdropyrimidine-4- carboxylic acid
• Step 3 Ethyl 5-ethoxy-2-hvdroxy-l-methyl-6-oxo-1.6-dihvdropyrimidine-4- carboxylate
• Step 4 Ethyl 2-chloro-5-ethoxy-l-methyl-6-oxo-l,6-dihvdropyrimidine-4- carboxylate
• Ethyl 2-chloro-5-ethoxy-l-methyl-6-oxo-l,6-dihydropyrimidine-4- carboxylate (1 eq), 2-furanboronic acid (1.1 eq), bis(tri-£ert- butylphosphine)palladium(O) (0.015 eq) and spray-dried potassium fluoride (3.3 eq) were placed in an oven-dried Schlenk tube and purged with argon. Anhydrous 1,4-dioxane (0.3 M solution) was added and the reaction mixture was purged with three vacuum/argon cycles before being heated at 85°C under an inert atmosphere for 3 h.
• Step 6 2-(Furan-2-yl)-5-hvdroxy-l-methyl-6-oxo-l,6-dihvdropyrimidine-4- carboxylic acid
• a solution of ethyl 5-ethoxy-2-(furan-2-yl)-l-methyl-6-oxo-l,6- dihydropyrimidine-4-carboxylate (1 eq) in anhydrous methylene chloride (0.2 M solution) was treated dropwise with a 1 M solution of boron tribromide (5 eq). The reaction mixture was stirred for 1 hour at room temperature.
• Step 1 Ethyl 5-ethoxy-2-(3-formylfuran-2-yl ) -l-methyl-6-oxo-1.6- dihvdropyrimidine-4-carboxylate
• Step 2 Ethyl 5-ethoxy-l-methyl-6-oxo-2- ⁇ 3-r( )-2-phenylethenyllfuran-2- yl ⁇ -l,6-dihvdropyrimidine-4-carboxylate
• Step 1 Ethyl 5-ethoxy-l-methyl-6-oxo-2-r( ' trimethylsilyl)ethvnvn-1.6- dihydropyrimidine-4-carboxylate
• Step 2 Dimethyl 2-((r(lZ)-(r2-(2-chlorophenyl)ethvnaminoUthien-2- yl)methylidene1amino ⁇ oxy)but-2-enedioate
• Step 3 Methyl l-r2-(2-chlorophenyl)ethyll-5-hvdroxy-6-oxo-2-(thien-2-yl)- l,6-dihydropyrimidine-4-carboxylate
• Step 4 l-r2-(2-Chlorophenv ethvn-5-hvdroxy-6-oxo-2-(thien-2-yl)-1.6- dihydropyrimidine-4-carboxylic acid
• Methyl l-[2-(2-chlorophenyl)ethyl]-5-hydroxy-6-oxo-2-(thien-2-yl)- l,6-dihydropyrimidine-4-carboxylate was dissolved in a 4:1 mixture of THF/water (0.02 M). Lithium hydroxide (5.0 eq) was added and the mixture was heated at 40°C for 4 h. The cooled mixture was acidified to pH 2 and the white precipitate purified by RP-HPLC (column: Symmetry C 18 19 x 100 mm 5 ⁇ m) to afford the title compound (80%).
• Example 42 Following generally the procedures outlined in Example 42, the title compound was obtained from ⁇ -hydroxythiophene-2-carboximidoyl chloride and 2,2,2-trifluoroethylamine as a colourless solid. ⁇ H (400 MHz;
• Step 2 5-Hvdroxy-l-methyl-2- 3-([2-(l-naphthyl)ethvnsulfonylamino)- thien-2-yll-6-oxo-1.6-dihydropyrimidine-4-carboxylic acid 2-(l-Naphthyl)ethanesulphonyl chloride (2 eq) was added to a stirred solution of methyl 2-(3-aminothien-2-yl)-5-hydroxy-l-methyl-6-oxo- l,6-dihydropyrimidine-4-carboxylate and NaOH (1 N) (2 eq) in THF (0.16 N). The reaction mixture was stirred at room temperature.
• Step 1 Methyl 5-t6rt-butoxy-l-methyl-2-(3-nitrothien-2-yl)-6-oxo-1.6- dihydropyrimidine-4-carboxylate 0-teri-Butyl-N,N'-diisopropylisourea (5 eq) was added to a solution of methyl 5-hydroxy-l-methyl-2-(3-nitrothien-2-yl)-6-oxo-l,6- dihydropyrimidine-4-carboxylate (obtained as described in Example 27, step 3) in THF (0.4 M).
• Step 2 Methyl 5-tert-butoxy-l-methyl-2-(3-aminothien-2-yl)-6-oxo-l,6- dihydropyrimidine-4-carboxylate
• Triphosgene (1.5 eq) was added to a solution of the foregoing compound in dry 1,4-dioxane.
• the flask was continuously purged with nitrogen and the effluent was bubbled through aqueous KOH solution to destroy excess phosgene.
• (2-phenyl-l,3-thiazol-4- yl)methylamine (3 eq) was added and the mixture was stirred 3 h at room temperature. After dilution with water it was extracted with EtOAc. The collected organic layers were treated with brine and dried on Na2S0 4 .
• Step 4 5-Hvdroxy-l-methyl-6-oxo-2- ⁇ 3-r((r(2-phenyl-1.3-thiazol-4- yl)methyllamino)carbonyl)aminolthien-2-yl ⁇ -l,6-dihydropyrimidine-4- carboxylic acid
• Step 1 t ⁇ rt-Butyl 5-t ⁇ rt-butoxy-2-r3-( ⁇ [(2-chlorobenzyl)oxy]carbonyl
• Step 2 2-[3-( ⁇ r(2-Chlorobenzyl)oxy1carbonyl)amino)thien-2-yl1-5-hydroxy-l- methyl-6-oxo-l,6-dihvdropyrimidine-4-carboxylic acid

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